A1 adenosine receptor agonists

Abstract

Disclosed are novel compounds that are partial and full A 1 adenosine receptor agonists having the structure of Formula I: which are useful for treating various disease states, in particular tachycardia and atrial flutter, angina, and myocardial infarction.

1 . A compound having the structure of Formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is hydroxymethyl, —C(O)OR 6 , or —C(O)NHR 6 , in which R 6  is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 2  is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl; 
 R 3 , R 4 , and R 5  are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, —CO 2 H, —SO 3 H, —C(O)OR 6 , —CH(OH)R 6 , or C(O)NR 6 R 7 , wherein R 7  is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, optionally substituted aryl, or optionally substituted heteroaryl, 
 
       or a salt, hydrate, or pharmaceutically acceptable ester thereof. 
     
     
         2 . The compound of  claim 1 , wherein R 2  is an optionally substituted heterocyclic moiety. 
     
     
         3 . The compound of  claim 2 , wherein R 2  is an optionally substituted five membered heterocyclic ring having at least one nitrogen or oxygen atom. 
     
     
         4 . The compound of  claim 3 , wherein R 3  and R 5  are hydrogen or optionally substituted lower alkyl. 
     
     
         5 . The compound of  claim 4 , wherein R 4  is optionally substituted aryl. 
     
     
         6 . The compound of  claim 5 , selected from the group consisting of: 
       2-(6-[((3R)oxolan-3-yl)amino]-2-{4-[4-(trifluoromethyl)phenyl]pyrazolyl}purin-9-yl)(4S,2R,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol; 
       5-{6-[((3R)oxolan-3-yl)amino]-2-[4-(4-methylphenyl)pyrazolyl]purin-9-yl}(2S,4S,3R,5R)-3,4-dihydroxyoxolane-2-carboxylic acid; 
       (5-{6-[((3R)oxolan-3-yl)amino]-2-[4-(4-methylphenyl)pyrazolyl]purin-9-yl}(2S,4S,3R,5R)-3,4-dihydroxyoxolan-2-yl)-N-ethylcarboxamide; and 
       5-(hydroxymethyl)-2-{2-[4-(4-methylphenyl)pyrazolyl]-6-(oxolan-3-ylamino)purin-9-yl}oxolane-3,4-diol. 
     
     
         7 . The compound of  claim 4 , wherein R 4  is optionally substituted heteroaryl. 
     
     
         8 . The compound of  claim 7 , selected from the group consisting of: 
       (5-{6-[((3R)oxolan-3-yl)amino]-2-(4-(4-pyridyl)pyrazolyl)purin-9-yl}(2S,4S,3R,5R)-3,4-dihydroxyoxolan-2-yl)-N-ethylcarboxamide; 
       (5-{6-[((3R)oxolan-3-yl)amino]-2-(4-(2-quinolyl)pyrazolyl)purin-9-yl}(2S,4S,3R,5R)-3,4-dihydroxyoxolan-2-yl)-N-ethylcarboxamide; 
       6-(1-{6-[((3R)oxolan-3-yl)amino]-9-[3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)pyridine-3-carboxylic acid; 
       2-{6-[((3R)oxolan-3-yl)amino]-2-(4-pyrazin-2-ylpyrazolyl)purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol; 
       2-{6-[((3R)oxolan-3-yl)amino]-2-(4-quinazolin-2-ylpyrazolyl)purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol; 
       2-{6-[((3R)oxolan-3-yl)amino]-2-(4-(2-pyridyl)pyrazolyl)purin-9-yl}(4S,3R)-5-(hydroxymethyl)oxolane-3,4-diol; 
       2-{6-[((3R)oxolan-3-yl)amino]-2-(4-(4-pyridyl)pyrazolyl)purin-9-yl}(4S,3R)-5-(hydroxymethyl)oxolane-3,4-diol; and 
       2-{6-[((3R)oxolan-3-yl)amino]-2-(4-(2-quinolyl)pyrazolyl)purin-9-yl}(4S,3R)-5-(hydroxymethyl)oxolane-3,4-diol. 
     
     
         9 . The compound of  claim 4 , wherein R 4  is —CO 2 H, —SO 3 H, —C(O)OR 6 , —CH(OH)R 6 , or C(O)NR 6 R 7 . 
     
     
         10 . The compound of  claim 9 , selected from the group consisting of: 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(oxolan-3-ylamino)purin-2-yl}pyrazol-4-yl)-N-[(4-fluorophenyl)sulfonyl]carboxamide; 
       methyl 4-{(1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)carbonylamino]methyl}benzoate; 
       4-{[((1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)carbonylamino]methyl}benzoic acid; 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-[(4-chlorophenyl)methyl]carboxamide; 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-[(4-fluorophenyl)methyl]carboxamide; 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-benzylcarboxamide; 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(3S,2R,4R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-{[5-fluoro-3-(trifluoromethyl)phenyl]methyl}carboxamide; 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-propylcarboxamide; 
       ethyl 1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazole-4-carboxylate; 
       1-{6-((3R)oxolan-3-yl)amino-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazole-4-carboxylic acid; 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-methylcarboxamide; and 
       (1-{6-[((3R)oxolan-3-yl)amino]-9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-ethylcarboxamide. 
     
     
         11 . The compound of  claim 4 , wherein R 4  is hydrogen or optionally substituted alkyl. 
     
     
         12 . The compound of  claim 11 , namely 2-{6-[((3R)oxolan-3-yl)amino]-2-[4-(hydroxyphenylmethyl)pyrazolyl]purin-9-yl}(4S,2R,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol. 
     
     
         13 . The compound of  claim 1 , wherein R 2  is an optionally substituted cycloalkyl moiety. 
     
     
         14 . The compound of  claim 13 , wherein R 3  and R 5  are hydrogen or optionally substituted lower alkyl. 
     
     
         15 . The compound of  claim 14 , wherein R 4  is —CO 2 H, —SO 3 H, —C(O)OR 6 , —CH(OH)R 6 , or C(O)NR 6 R 7 . 
     
     
         16 . The compound of  claim 15 , selected from the group consisting of: 
       ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylate; 
       1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxy methyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxylic acid; 
       1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxamide; 
       ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(bicyclo[2.2.1]hept-2-ylamino)purin-2-yl}pyrazole-4-carboxylate; 
       1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(bicyclo[2.2.1]hept-2-ylamino)purin-2-yl}pyrazole-4-carboxylic acid; 
       (1-{9-(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-methylcarboxamide; 
       1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-5-methylpyrazole-3-carboxamide; 
       (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}-5-methylpyrazol-3-yl)-N-methylcarboxamide; 
       ethyl 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclohexylamino)purin-2-yl}pyrazole-4-carboxylate; 
       (1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclohexylamino)purin-2-yl}pyrazol-4-yl)-N-methylcarboxamide; 
       ethyl 1-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazole-4-carboxylate; 
       1-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazole-4-carboxylic acid; 
       (1-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazol-4-yl)-N-methylcarboxamide; 
       1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclohexylamino)purin-2-yl}pyrazole-4-carboxamide; 
       1-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl}pyrazole-4-carboxamide; 
       1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclohexylamino)purin-2-yl}pyrazole-4-carboxylic acid; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-[(4-fluorophenyl)sulfonyl]carboxamide; 
       methyl 2-{[(1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)carbonylamino]sulfonyl}benzoate; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-(ethylsulfonyl)carboxamide; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-[(2-chlorophenyl)sulfonyl]carboxamide; 
       (1-{9-{[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl)}pyrazol-4-yl)-N-(3,3,3-trimethyl-3-azabutyl)carboxamide; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-[(4-methylphenyl)sulfonyl]carboxamide; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-[benzylsulfonyl]carboxamide; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-(phenylsulfonyl)carboxamide; 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-{[4-(trifluoromethyl)phenyl]sulfonyl}carboxamide; and 
       (1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-[(3-chlorophenyl)sulfonyl]carboxamide. 
     
     
         17 . The compound of  claim 14 , wherein R 4  is hydrogen or optionally substituted alkyl, alkenyl, or alkynyl. 
     
     
         18 . The compound of  claim 17 , selected from the group consisting of: 
       (4S,3R,5R)-2-[2-(3,5-dimethylpyrazolyl)-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol; 
       (4S,3R,5R)-2-[2-(3,5-dimethyl-4-propylpyrazolyl)-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol; 
       (4S,3R,5R)-2-[2-(4-butyl-3,5-dimethylpyrazolyl)-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol; 
       (4S,3R,5R)-2-[6-(bicyclo[2.2.1]hept-2-ylamino)-2-pyrazolylpurin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol; 
       (4S,3R,5R)-2-[6-(cyclopentylamino)-2-pyrazolylpurin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol; 
       1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carbonitrile; 
       ethyl (2E)-3-(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)prop-2-enoate; 
       ethyl 3-(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)propanoate; 
       (4S,3R,5R)-2-[6-(cyclohexylamino)-2-pyrazolylpurin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol; 
       3-(1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)-N-methylpropanamide; 
       2-{6-[((1R,2R)-2-hydroxycyclopentyl)amino]-2-pyrazolylpurin-9-yl}(2R,5R)-5-(hydroxymethyl)oxolane-3,4-diol; 
       (2R,5R)-2-{2-[4-(aminomethyl)pyrazolyl]-6-(cyclopentylamino)purin-9-yl}-5-(hydroxymethyl)oxolane-3,4-diol; and 
       [(1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazol-4-yl)methyl][(4-fluorophenyl)sulfonyl]amine. 
     
     
         19 . The compound of  claim 1 , wherein R 2  is an optionally substituted aryl or benzyl. 
     
     
         20 . The compound of  claim 19 , wherein R 3  and R 5  are hydrogen or optionally substituted lower alkyl. 
     
     
         21 . The compound of  claim 20 , wherein R 4  is —CO 2 H, —SO 3 H, —C(O)OR 6 , —CH(OH)R 6 , or C(O)NR 6 R 7 . 
     
     
         22 . The compound of  claim 21 , selected from the group consisting of: 
       ethyl 1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-[benzylamino]purin-2-yl}pyrazole-4-carboxylate; 
       (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-[benzylamino]purin-2-yl}pyrazol-4-yl)-N-propylcarboxamide; 
       (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-[benzylamino]purin-2-yl}pyrazol-4-yl)-N-ethylcarboxamide; 
       (1-{9-[(4S,2R,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-[benzylamino]purin-2-yl)}pyrazol-4-yl)-N-methylcarboxamide; and 
       4-({9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-2-[4-(ethoxycarbonyl)pyrazolyl]purin-6-yl}amino)benzenesulfonic acid. 
     
     
         23 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient and a therapeutically effective amount of a compound of  claim 1 .